One goal of this project is to better understand the mechanisms of the ionic conductances in membranes which are voltage dependent, i.e., excitable. Another goal is to determine how drugs influence these channels. These studies involve the use of the squid giant axon, neuroblastoma cells, and the giant barnacle muscle fiber. We have observed that in the squid axon, the local anesthetic, QX314, exhibits inhibition of the sodium current which is even further inhibited with a series of pulses following in rapid succession. The qualitative aspects of this use-dependent inhibition is similar to the use-dependent inhibition by yohimbine. In addition, we found that both QX314 and yohimbine act as competitive inhibitors of the channel-opener drug, batrachotoxin, in neuroblastoma cells. The data can be fit by a model wherein yohimbine or a local anesthetic such as QX314 bind to open sodium channels and that the drug-bound channels have a different rate of opening and closing than the normal sodium channels.